Platelet aggregation supposedly causes various circulatory diseases and inhibitors of platelet aggregation have occupied an important position among drugs.
The representative substances known to induce platelet aggregation are adenosine diphosphate (ADP) and metabolites of arachidonic acid such as thromboxane A.sub.2 (TXA.sub.2) in particular. Accordingly in the development of platelet aggregation inhibitors, the inhibition of the activity of these substances has been utilized as a primary screening indicator.
Recently, however, as a substance that displays a stronger platelet aggregation effect via a different mode of action from that of ADP and TXA.sub.2, platelet activating factor (PAF) was discovered and its structure has been identified to be 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine [Nature, 285, 193 (1980)]. It has been found that PAF has a mode of action different from that of ADP and TXA.sub.2 and displays greater activity at lower concentrations. Moreover, PAF is a strong chemical transmitter of allergy and in the assay using respiratory stenosis as an indicator, this substance has been found to have the highest activity of all the known compounds [European Journal of Pharmacology, 65, 185-192 (1980)]. It is, therefore, logical to assume that if a compound inhibits the action of PAF, it could be an effective inhibitor of platelet aggregation and also be an effective drug against PAF-induced diseases such as allergies.
It is also known that PAF functions as a shock inducer [European Journal of Pharmacology, 86, 403-413 (1983)]. Shocks may arise from various causes. They may be traumatic, hemorrhagic, cardiogenic, bacterial and so on. However, the pathological condition of shock is almost the same irrespective of causes; thus, circulatory disorders such as hypotension, decreased cardiac output, etc., and such metabolic disorders as metabolic acidosis, hyperpotassemia and lactacidemia are observed. Taking bacterial shock as an example, it is most often caused by infection of gram-negative bacilli (Escherichia coli, Pseudomonas aeruginosa, Krebsiella, etc.) and an endotoxin which is a cell wall component of these bacteria is said to be the causative agent. Actually, a shock can be induced by injecting the endotoxin into animals. Despite progresses in antibiotic and transfusion therapies, the rate of mortality due to shock has not been reduced. Therefore, when a shock is foreseen, antibiotics are administered in combination with a drug for preventing endotoxin shocks. Among the drugs commonly used for the purpose are adrenocortical hormones such as hydrocortisone, dexamethazone, etc. However, since this type of drug is given in high doses in cases of shock, the onset of side effects presents a problem. Antiinflammatory agents such as indomethacin have also been employed but they may cause ulceration and other untoward side effects and their efficacy is not distinct, either.
The present inventors investigated the methods for inhibiting the actions of PAF associated with various circulatory diseases and allergic diseases and have completed the present invention.